Abigail G. Doyle

Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp3-carbons with aryl halides

A bright outlook for carbon coupling In contemporary organic chemistry, it is straightforward to forge bonds between unsaturated carbons (i.e., carbons already engaged in double bonds) using cross-coupling catalysis. The protocol runs into some trouble, however, if one or both starting carbon centers are saturated (purely single-bonded). Tellis et al. and Zuo et al. independently found that combining a second, light-activated catalyst with a nickel cross-coupling catalyst could achieve selective coupling of saturated and unsaturated reagents (see the Perspective by Lloyd-Jones and Ball). Their methods rely on single-electron transfer from the light-activated catalyst to the saturated carbon, thereby enhancing its reactivity more effectively than the twoelectron mechanisms prevailing in traditional protocols. Science, this issue p. 433, p. 437; see also p. 381 Combining two catalysts, one light-activated, facilitates bond formation between saturated and unsaturated carbons. [Also see Perspective by Lloyd-Jones and Ball] Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp2) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp3) carbons have proven more challenging. Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available organic molecules can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, we have achieved a direct decarboxylative sp3–sp2 cross-coupling of amino acids, as well as α-O– or phenyl-substituted carboxylic acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct cross-coupling of Csp3–H in dimethylaniline with aryl halides via C–H functionalization.

Enantioselective Thiourea-Catalyzed Additions to Oxocarbenium Ions

Asymmetric, catalytic reactions of oxocarbenium ions are reported. Simple, chiral urea and thiourea derivatives are shown to catalyze the enantioselective substitution of silyl ketene acetals onto 1-chloroisochromans. A mechanism involving anion binding by the chiral catalyst to generate a reactive oxocarbenium ion is invoked. Catalysts bearing tertiary benzylic amide groups afforded highest enantioselectivities, with the optimal structure being derived from enantioenriched 2-arylpyrrolidine derivatives.

Enantioselective Ring Opening of Epoxides by Fluoride Anion Promoted by a Cooperative Dual-Catalyst System

An enantioselective method for the synthesis of beta-fluoroalcohols by catalytic nucleophilic fluorination of epoxides is described. Mild reaction conditions and high selectivity are made possible by the use of benzoyl fluoride as a soluble, latent source of fluoride anion. A chiral amine and chiral Lewis acid serve as cooperative catalysts for desymmetrizations of five- through eight-membered cyclic epoxides, affording products in up to 95% ee. The cocatalytic protocol is also effective for kinetic resolutions of racemic terminal epoxides, which proceed with k(rel) values as high as 300.

Palladium-Catalyzed Asymmetric Synthesis of Allylic Fluorides

The enantioselective fluorination of readily available cyclic allylic chlorides with AgF has been accomplished using a Pd(0) catalyst and Trost bisphosphine ligand. The reactions proceed with unprecedented ease of operation for Pd-mediated nucleophilic fluorination, allowing access to highly enantioenriched cyclic allylic fluorides that bear diverse functional groups. Evidence that supports a mechanism in which C-F bond formation occurs by an S(N)2-type attack of fluoride on a Pd(II)-allyl intermediate is presented.

Palladium-catalyzed allylic C-H fluorination.

The first catalytic allylic C-H fluorination reaction using a nucleophilic fluoride source is reported. Under the influence of a Pd/Cr cocatalyst system, simple olefin substrates undergo fluorination with Et3N·3HF in good yields with high branched:linear regioselectivity. The mild conditions and broad scope make this reaction a powerful alternative to established methods for the preparation of allylic fluorides from prefunctionalized substrates.

Palladium-Catalyzed Regio- and Enantioselective Fluorination of Acyclic Allylic Halides

This report describes the Pd(0)-catalyzed fluorination of linear allylic chlorides and bromides, yielding branched allylic fluorides in high selectivity. Many of the significant synthetic limitations previously associated with the preparation of these products are overcome by this catalytic method. We also demonstrate that a chiral bisphosphine-ligated palladium catalyst enables highly enantioselective access to a class of branched allylic fluorides that can be readily diversified to valuable fluorinated products.

Mechanistic investigations of cooperative catalysis in the enantioselective fluorination of epoxides.

This report describes mechanistic studies of the (salen)Co- and amine-cocatalyzed enantioselective ring opening of epoxides by fluoride. The kinetics of the reaction, as determined by in situ (19)F NMR analysis, are characterized by apparent first-order dependence on (salen)Co. Substituent effects, nonlinear effects, and reactivity with a linked (salen)Co catalyst provide evidence for a rate-limiting, bimetallic ring-opening step. To account for these divergent data, we propose a mechanism wherein the active nucleophilic fluorine species is a cobalt fluoride that forms a resting-state dimer. Axial ligation of the amine cocatalyst to (salen)Co facilitates dimer dissociation and is the origin of the observed cooperativity. On the basis of these studies, we show that significant improvements in the rates, turnover numbers, and substrate scope of the fluoride ring-opening reactions can be realized through the use of a linked salen framework. Application of this catalyst system to a rapid (5 min) fluorination to generate the unlabeled analog of a known PET tracer, F-MISO, is reported.

Nickel-Catalyzed Negishi Alkylations of Styrenyl Aziridines

A nickel-catalyzed cross-coupling reaction between N-sulfonyl aziridines and organozinc reagents is reported. The catalytic system comprises an inexpensive and air-stable Ni(II) source and dimethyl fumarate as ligand. Regioselective synthesis of β-substituted amines is possible under mild and functional-group-tolerant conditions. The stereoselectivity of the reaction is consistent with a stereoconvergent mechanism wherein the sulfonamide directs C-C bond formation.

Direct Acylation of C(sp3)−H Bonds Enabled by Nickel and Photoredox Catalysis

Using nickel and photoredox catalysis, the direct functionalization of C(sp(3))-H bonds of N-aryl amines by acyl electrophiles is described. The method affords a diverse range of α-amino ketones at room temperature and is amenable to late-stage coupling of complex and biologically relevant groups. C(sp(3))-H activation occurs by photoredox-mediated oxidation to generate α-amino radicals which are intercepted by nickel in catalytic C(sp(3))-C coupling. The merger of these two modes of catalysis leverages nickels unique properties in alkyl cross-coupling while avoiding limitations commonly associated with transition-metal-mediated C(sp(3))-H activation, including requirements for chelating directing groups and high reaction temperatures.

Synthesis of β-Fluoroamines by Lewis Base Catalyzed Hydrofluorination of Aziridines

Lewis base catalysis promotes the in situ generation of amine-HF reagents from benzoyl fluoride and a non-nucleophilic alcohol. The hydrofluorination of aziridines to provide β-fluoroamines using this latent HF source is described. This protocol displays a broad scope with respect to aziridine substitution and N-protecting groups. Examples of regio- and diastereoselective ring opening to access medicinally relevant β-fluoroamine building blocks are presented.